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Title: Cognitive function, the brain and glucocorticoids
Author: MacLullich, Alasdair Maurice Joseph
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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Several domains of cognitive function show lower mean scores and increasing variability with increasing age. Little is known about the biological mechanisms underlying these changes. There is evidence, largely from animal studies, that prolonged exposure to high levels of glucocorticoids is associated with (a) atrophy of brain regions known to be essential for cognitive functioning, such as the hippocampus, and (b) decrements in cognitive function with ageing. There are few human studies examining these links. The studies in this thesis were aimed at testing the hypotheses that elevated levels in Cortisol are associated with relative cognitive impairment, with relative atrophy of the hippocampus and other brain regions, and also with variations in the levels of brain metabolites, and also that cognitive function is associated with brain size and metabolites. Additionally, measures of glucose homeostasis (fasting glucose and glycosylated haemoglobin (HbAlc)) were hypothesised to be negatively correlated with cognitive function. Ill healthy, unmedicated men aged 65-70 were recruited. Subjects had blood taken for 9am, 2.30pm, and post-dexamethasone (0.25mg) Cortisol levels, fasting glucose, and HbAlc, and did a battery of cognitive tests, including tests of 'premorbid' intelligence, fluid intelligence, verbal and visuospatial memory and processing speed. 100 of the subjects underwent two modalities of neuroimaging: (a) structural magnetic resonance imaging, with intracranial area, hippocampus, temporal lobe and frontal lobe volumes measured, and (b) magnetic resonance spectroscopy (MRS), with N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) levels measured. Principal components analyses showed that a single component (designated the 'general cognitive factor') accounted for 51% of the variance in cognitive performance; rotation yielded two correlated components representing fluid intelligence/visuospatial memory tasks, and verbal memory tasks. Intracranial area and several regional brain volumes correlated positively and significantly with 'premorbid' and fluid intelligence and visuospatial memory. Verbal memory and verbal fluency did not correlate significantly with any brain volumes. Structural equation modelling showed that the relationships between cognitive tests and brain volumes could best be summarised by a significant positive relationship between overall brain size and the general cognitive factor (r=0.42, p < 0.05), and not by associations between individual tests and particular brain regions. Both NAA/Cr and Cho/Cr ratios correlated positively with tests of verbal memory and a verbal memory factor (e.g. NAA/Cr and Logical Memory: r=0.24, p < 0.05). Cho/Cr ratios also correlated positively with visuospatial memory (eg. Visual Reproduction: r=0.21, p < 0.05). There were several small but statistically significant correlations in the predicted (negative) direction between brain volumes and Cortisol levels. Left temporal lobe volumes correlated with 9am Cortisol (r=-0.22) and 2.30pm Cortisol (r=-0.26), right temporal lobe volumes correlated with 9am Cortisol (r=-0.21), right hippocampal volumes correlated with 9am Cortisol (r=-0.22) and postdexamethasone Cortisol (r=-0.24). These correlations were significant at p < 0.05, 2- tailed. There were no significant correlations between Cortisol measures and metabolite ratios (from MRS). Correlations between Cortisol measures and cognitive tests were largely in the predicted direction, though few of these correlations reached conventional levels of statistical significance. The general cognitive factor and the fluid/intelligence factor, adjusted for 'premorbid' intelligence, correlated significantly and negatively with 9am Cortisol levels, at r=-0.23 (p=0.028, 2-tailed). HbAlc was significantly negatively correlated with two measures of verbal memory, but not with other cognitive tests (list-learning: r=-0.24, p=0.01; delayed paragraph recall r=-0.31, p=0.018, 2-tailed). These results demonstrate that in healthy, elderly men, overall brain size and metabolite ratios are significantly related to cognitive ability. A possible mechanistic link between these two domains is variations in Cortisol with ageing. The results of the present studies are supportive of the hypothesis that elevated glucocorticoids are associated with ageing-related changes in brain volumes, and, less clearly, cognitive function. Follow-up studies will help determine whether Cortisol levels are predictive of worsening brain atrophy and cognitive decline.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available